The Receptor Binding Domain of Apolipoprotein E, Linked to a Model Class A Amphipathic Helix, Enhances Internalization and Degradation of LDL by Fibroblasts

Datta, Geeta; Chaddha, Manjula; Garber, David W.; Chung, Byung Hong; Tytler, Ewan M.; Dashti, Nassrin; Bradley, William A.; Gianturco, Sandra H.; Anantharamaiah, G.M.

doi:10.1021/bi991209w

Cited by 76 publications

(90 citation statements)

References 35 publications

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“…Peptide m18L with the sequence Ac-G-F-K-K-F-L-G-S-W-A-K-I-Y-K-A-F-V-G-NH 2 and its Arg analog (mR18L; all of the Lys in m18L replaced by Arg) were synthesized by the solid phase peptide synthesis method using fl uorenylmethyloxycarbonyl (FMOC) amino acids and suitable protected amino acids as described previously ( 13 ). The peptides were purifi ed by preparative HPLC, and the purity and identity of the peptides were determined by analytical HPLC and mass spectra.…”

Section: Methodsmentioning

confidence: 99%

“…On the basis of the idea that apoE possesses the putative receptor binding domain (141-155 region of apoE) at the N-terminus and a lipid binding domain at the C terminus, we designed a dual-domain peptide Ac-hE18A-NH 2 in which residues 141-150 of apoE, LRKLRKRLLR, is covalently bound to the model class A peptide 18A ( 2 ). This peptide is capable of reducing plasma cholesterol via hepatic uptake and has anti-infl ammatory properties (13)(14)(15). However, this peptide has only been shown to be active when intravenously administered.…”

Section: Right-angle Light Scattering Measurementsmentioning

confidence: 99%

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Oral administration of L-mR18L, a single domain cationic amphipathic helical peptide, inhibits lesion formation in ApoE null mice

Handattu

Datta

Epand

et al. 2010

Journal of Lipid Research

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Supplementary key words atherosclerosis • metabolism • animals • lipids • cholesterolAs apolipoprotein (apo)A-I possesses tandem repeating class A amphipathic helical motifs, several investigators (including our own laboratory) have developed peptides that possess the class A amphipathic helical motif and have shown that, similar to apoA-I, several of these peptides not only interact with phospholipids to form nascent HDL-like peptide-lipid discoidal complexes but also possess both anti-infl ammatory and cellular cholesterol effl uxing properties ( 1-3 ). Several papers have been published using 4F and D-4F peptides to demonstrate that the peptides inhibit or slow down the onset of several infl ammatory diseases, including atherosclerosis (reviewed in Ref. 4 ). When 4F is synthesized from all D amino acids, the resulting D-4F is orally active and can be administered either in drinking water or mixed with food to inhibit infl ammatory processes ( 5 ). However, not all of the class A peptides are antiinfl ammatory ( 6, 7 ). It has been shown that the clustering of aromatic residues on the nonpolar face of a class A amphipathic helical motif favors its association with oxidized phospholipid ( 6-9 ).An ideal strategy for inhibiting atherosclerosis would not only decrease plasma cholesterol levels but also increase anti-infl ammatory properties. ApoE, the protein Abstract We have shown that Ac-hE18A-NH 2 , a dual-domain cationic apolipoprotein-mimetic peptide, reduces plasma cholesterol levels in dyslipidemic mice. Two singledomain cationic peptides based on the lytic class L peptide 18L were developed to test the hypothesis that a singledomain cationic amphipathic peptide can reduce atherosclerosis in apolipoprotein (apo)E null mice when orally administered. To incorporate anti-infl ammatory properties, aromatic residues were clustered in the nonpolar face similar to peptide 4F, resulting in modifi ed 18L (m18L). To reduce lytic properties, the Lys residues of 18L were replaced with Arg with the resulting peptide called modifi ed R18L (mR18L). Biophysical studies showed that mR18L had stronger interactions with lipids than did m18L. Peptide mR18L was also more effective than m18L in promoting LDL uptake by HepG2 cells. ApoE null mice received normal chow or chow containing m18L or mR18L for six weeks. A signifi cant reduction in plasma cholesterol and aortic sinus lesion area was seen only in the mR18L group. Plasma from mice administered mR18L, unlike those from the control and m18L groups, did not enhance monocyte adhesion to endothelial cells. Thus oral administration of mR18L reduces plasma cholesterol and lesion formation and inhibits monocyte adhesion. -Handattu, S. P., G. Datta, R. M. Epand, R.

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Section: Methodsmentioning

confidence: 99%

Section: Right-angle Light Scattering Measurementsmentioning

confidence: 99%

Oral administration of L-mR18L, a single domain cationic amphipathic helical peptide, inhibits lesion formation in ApoE null mice

Handattu

Datta

Epand

et al. 2010

Journal of Lipid Research

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“…ApoE is associated with VLDL and HDL. It contains a lipid associating domain and a globular domain containing the LDL receptor binding site [89]. The presence of the LDL receptor domain facilitates the hepatic clearance of cholesteryl esters, resulting in a significant decrease in plasma total cholesterol [90].…”

Section: New Directions In Apolipoprotein Mimetic Peptide Designmentioning

confidence: 99%

“…The presence of the LDL receptor domain facilitates the hepatic clearance of cholesteryl esters, resulting in a significant decrease in plasma total cholesterol [90]. A peptide encoding an arginine-rich region (residues 141-150: LRKLRKRLLR) of the putative LDL receptor binding sequence, linked to 18A, has been synthesized [89,91]. The peptide was acetylated and amidated at the C-and Ntermini respectively to yield the stabilized peptide Ac-hE[141-150]18A-NH 2 (Ac-hE18A-NH 2 ).…”

Section: New Directions In Apolipoprotein Mimetic Peptide Designmentioning

confidence: 99%

“…The peptide was acetylated and amidated at the C-and Ntermini respectively to yield the stabilized peptide Ac-hE[141-150]18A-NH 2 (Ac-hE18A-NH 2 ). Ac-hE18A-NH 2 associates with LDL and VLDL and targets these lipoproteins to hepatocytes for clearance via binding to heparan sulfate proteoglycans (HSPG) [89,91]. This effect is similar to increasing the addition of apo E to the surface of VLDL which redirects VLDL to HSPG for enhanced uptake by hepatocytes.…”

Section: New Directions In Apolipoprotein Mimetic Peptide Designmentioning

confidence: 99%

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Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm in HDL Therapy

White¹,

Datta²,

Mochon³

et al. 2009

VDP

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Anti-atherogenic effects of high density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) are principally thought to be due to their ability to mediate reverse cholesterol transport. These agents also possess anti-oxidant properties that prevent the oxidative modification of low density lipoprotein (LDL) and anti-inflammatory properties that include inhibition of endothelial cell adhesion molecule expression. Results of the Framingham study revealed that a reduction in HDL levels is an independent risk factor for coronary artery disease (CAD). Accordingly, there has been considerable interest in developing new therapies that specifically elevate HDL cholesterol. However, recent evidence suggests that increasing circulating HDL cholesterol levels alone is not sufficient as a mode of HDL therapy. Rather, therapeutic approaches that increase the functional properties of HDL may be superior to simply raising the levels of HDL per se. Our laboratory has pioneered the development of synthetic, apolipoprotein mimetic peptides which are structurally and functionally similar to apoA-I but possess unique structural homology to the lipid-associating domains of apoA-I. The apoA-I mimetic peptide 4F inhibits atherogenic lesion formation in murine models of atherosclerosis. This effect is related to the ability of 4F to induce the formation of pre-β HDL particles that are enriched in apoA-I and paraoxonase. 4F also possesses anti-inflammatory and anti-oxidant properties that are independent of its effect on HDL quality per se. Recent studies suggest that 4F stimulates the expression of the antioxidant enzymes heme oxygenase and superoxide dismutase and inhibits superoxide anion formation in blood vessels of diabetic, hypercholesterolemic and sickle cell disease mice. The goal of this review is to discuss HDL-dependent and -independent mechanisms by which apoA-I mimetic peptides reduce vascular injury in experimental animal models.

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Deconvolving Passive and Active Targeting of Liposomes Bearing LDL Receptor Binding Peptides Using the Zebrafish Embryo Model

Bi,

Van Hal,

Aschmann

et al. 2024

Small

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Improving target versus off‐target ratio in nanomedicine remains a major challenge for increasing drug bioavailability and reducing toxicity. Active targeting using ligands on nanoparticle surfaces is a key approach but has limited clinical success. A potential issue is the integration of targeting ligands also changes the physicochemical properties of nanoparticles (passive targeting). Direct studies to understand the mechanisms of active targeting and off‐targeting in vivo are limited by the lack of suitable tools. Here, the biodistribution of a representative active targeting liposome is analyzed, modified with an apolipoprotein E (ApoE) peptide that binds to the low‐density lipoprotein receptor (LDLR), using zebrafish embryos. The ApoE liposomes demonstrated the expected liver targeting effect but also accumulated in the kidney glomerulus. The ldlra−/‐ zebrafish is developed to explore the LDLR‐specificity of ApoE liposomes. Interestingly, liver targeting depends on the LDLR‐specific interaction, while glomerular accumulation is independent of LDLR and peptide sequence. It is found that cationic charges of peptides and the size of liposomes govern glomerular targeting. Increasing the size of ApoE liposomes can avoid this off‐targeting. Taken together, the study shows the potential of the zebrafish embryo model for understanding active and passive targeting mechanisms, that can be used to optimize the design of nanoparticles.

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The Receptor Binding Domain of Apolipoprotein E, Linked to a Model Class A Amphipathic Helix, Enhances Internalization and Degradation of LDL by Fibroblasts

Cited by 76 publications

References 35 publications

Oral administration of L-mR18L, a single domain cationic amphipathic helical peptide, inhibits lesion formation in ApoE null mice

Oral administration of L-mR18L, a single domain cationic amphipathic helical peptide, inhibits lesion formation in ApoE null mice

Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm in HDL Therapy

Deconvolving Passive and Active Targeting of Liposomes Bearing LDL Receptor Binding Peptides Using the Zebrafish Embryo Model

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